The second five-year renewal of the Southern Community Cohort Study (SCCS) is proposed in this grant application. Progress during the initial nine years of the study has been exceptional. We achieved a final cohort size of approximately 86,000 adults aged 40-79, two-thirds of whom are African American, with detailed baseline data assembled for all and biological specimens in frozen storage for nearly 90%. The cohort is now under follow-up for cancer mortality and incidence and other health outcomes. Historically, large-scale recruitment of African Americans, a group disproportionately burdened by cancer, into health research studies has been challenging. However, we uniquely overcame many known barriers to inclusion by developing partnerships with a network of southern Community Health Centers (CHCs), institutions that provide basic health services primarily to America's poor and uninsured. The SCCS thus differs from all other cohort studies in racial composition and socioeconomic disadvantage, and tracks a population possibly at higher cancer risk than any American population segment studied to date. Our specific aims for the renewal are (1) to continue passive follow-up of the cohort via linkages with various national and state registries to identify deaths, incident cancers and other health outcomes, (2) to continue active follow-up of the cohort via re-contact with participants to directly update exposure and health information, and (3) to conduct multiple new cohort and nested case-control analyses utilizing the baseline and follow-up data and stored DNA and blood specimens for evaluation of lifestyle, genetic and other risk or protective factors affecting the incidence of and disparities in the major cancers (lung, breast, prostate, and colon/rectum). We will evaluate hypotheses that the SCCS is uniquely or especially well positioned to address, many for the first time among African Americans, including the roles of obesity, vitamin D, specific infections (Chlamydia pneumoniae, Trichomonas vaginalis, Helicobacter pylori, and xenotropic murine leukemia virus-related virus), several nutrition-related pathways (one carbon metabolism, n-6 and n-3 polyunsaturated fatty acids and other dietary factors), cigarette mentholation, and use of the commonly prescribed glycemic control medication metformin, in relation to cancer risk and cancer disparities. PUBLIC HEALTH RELEVANCE: African Americans experience a disproportionate burden of cancer for reasons that are only partly understood, but most existing US cohort studies include only small numbers of African Americans, impeding ability to investigate cancer risk determinants among blacks and factors that might underlie cancer disparities. The Southern Community Cohort Study (SCCS), whose second renewal is proposed in this grant application, has completed enrollment, baseline data collection, and the development of a rich biospecimen repository, and is now poised to provide crucial information to fill these knowledge gaps. With continuation of both participant follow-up and the testing of innovative scientific hypotheses, the SCCS will enhance the collective scientific knowledge base and have a sustained and powerful impact aimed at the amelioration of health disparities.